Compositions that provide controlled delivery of pharmaceutical active agent offer several advantages. For instance, controlled delivery can reduce or obviate the need for repeated dosing. Further, biodegradable matrices for drug delivery are useful because they obviate the need to remove a drug-depleted device.
Noncompliance is prevalent with oral medications, e.g., in the treatment of schizophrenia and/or bipolar disorder. For instance, treatment of psychosis is very difficult. Patients cannot in general be relied upon to present for dosing or follow dosing instructions. It has also been established that the risk for relapse can substantially increase with noncompliant patients. Therefore, less complicated dosing and less frequent dosing is advantageous. Long-acting medications, e.g., antipsychotic medications, have several advantages over short-acting oral tablets or IM agents when administered, e.g., for the treatment of chronic schizophrenia and/or bipolar disorder, e.g., assurance of compliance resulting in fewer relapses and re-hospitalizations. By contrast, some of the current long-acting products (e.g., Risperdal Consta® long-acting injection) requires supplementation, e.g., with oral risperidone, both at the initiation of IM dosing and in the event of a missed dose, due to a 3-week lag between the time of dose administration and initiation of drug release.
All currently approved or development-stage, long-acting injections of antipsychotic drugs are administered intramuscularly, which is associated with the disadvantages of injection site pain and, for this class of drug, the more significant potential safety issue of inadvertent vascular contact resulting in systemic exposure of toxic levels of drug. This issue was most recently manifested during the development of Zyprexa® (olanzapine) long-acting-injection in which excessive sedation and even incidences of coma have been observed post injection. In contrast, dosage forms that have the potential for subcutaneous (SC) administration mitigate this potential safety issue.
As noted above, intramuscular dosing is in general painful, and requires a very large needle. For example, paliperidone palmitate (tradename Invega Sustenna) requires a needle that is 1″ long for patients <90 kg, and 1.5″ long for patient more than 90 kg. This can cause distress, especially in a psychotic patient, and can lead to difficulty in dosing and lack of compliance. Therefore, subcutaneous dosing is preferred.
Some long-acting therapies require a loading dose when the therapy is initiated to achieve a good release profile. A loading dose is an extra dose that is given early in a treatment regimen to compensate for inadequate control over plasma level before a sustained release formulation achieves steady state. Loading doses may be delivered orally or by injection. Loading doses are undesirable, especially in psychotic patients, as they may lead to additional anxiety, agitation, or lack of compliance with therapy. An example of a therapy requiring a loading dose is paliperidone palmitate (tradename Invega Sustenna). For paliperidone palmitate, one week after an initial injection, the patient is often given a further injection before transitioning to once a month dosing.
There remains, however, a need for compositions and methods that provide reproducible, controlled delivery of pharmaceutical active agents with low toxicity. Accordingly, there also remains a need for methods of making these compositions that provide reproducible, controlled delivery of pharmaceutical active agents with low toxicity.